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Periventricular nodular heterotopia

Orpha number ORPHA98892
Synonym(s) -
Prevalence Unknown
Inheritance Autosomal recessive
X-linked dominant
Age of onset -
ICD-10
  • Q04.8
ICD-O -
OMIM
UMLS
  • C1868720
MeSH
  • D054091
MedDRA
  • 10066854

Summary

Periventricular nodular heterotopia (PNH) is a brain malformation, due to abnormal neuronal migration, in which a subset of neurons fails to migrate into the developing cerebral cortex and remains as nodules that line the ventricular surface. Prevalence is unknown. The nodules can readily be detected with magnetic resonance imaging. Classical PNH is a rare X-linked dominant disorder far more frequent in females who present normal intelligence to borderline mental retardation, epilepsy of variable severity and extra-central nervous system signs, especially cardiovascular defects or coagulopathy. The disorder is generally associated with prenatal lethality in males, though few cases of males with X-linked PNH have been recently reported. These male subjects have high risk of aortic pathology. X-linked PNH has been demonstrated to be associated with mutations in the Filamin A gene (FLN1, FLNA or ABP-280). FLN1 maps to Xq28, and codes for Filamin A, which binds to actin and a wide range of cytoplasmic signalling proteins. Mutations of FLN1 have been found in 7/8 (87.5%) PNH pedigrees and in 6/31 (19%) and 2/24 (9%) sporadic female and male cases, respectively. The low percentage of FLN1 mutations in sporadic cases could be explained by somatic mosaicism, as well as the viability of some affected males. Recently a rare autosomal recessive form of PNH due to mutations of the ARFGEF2 gene and cases of individuals with PNH carrying a chromosomal rearrangement in 5p15.1 have been reported. Furthermore, other syndromes have been described, all occurring in sporadic boys, such as PNH with mental retardation and syndactyly and PNH with frontonasal malformation. Involvement of FLN1 in the latter syndromes has not yet been fully elucidated. Genetic counseling is relatively easy in familial cases with a clear X-linked pattern of inheritance. Classical PNH with cerebellar hypoplasia and no dysmorphic features is much more frequent in women and more likely to be due to FLN1 mutations than are atypical cases. Among carrier women, about half have de novo mutations of FLN1, while the remaining half have inherited mutations. Although maternal transmission is much more likely, father-to-daughter transmission is possible, implying that either parent can transmit the mutation to a female proband. An affected man with PNH caused by a FLN1 mutation would be expected to transmit the mutation to all his daughters, unless somatic mosaicism is present. If none of the parents has epilepsy or cognitive impairment, the proband's mother should be studied first, in order to confirm the mutation or the brain abnormality. If the mother is negative and the proband is a female, the father should also be studied. Since germline mosaicism of FLN1 has never been reported in PNH, the recurrence risk (for other children) seems to be low when a mutation is found in the proband but neither parent is a carrier. Management of individuals with periventricular heterotopia is based on symptomatic treatment, including medical therapy with antiepiletic drugs and surgical therapy for cardiovascular defects (most often persistent ductus of Botallo and aortic valvulopathy).

Expert reviewer(s)

  • Pr Renzo GUERRINI
  • Dr Elena PARRINI
  • Dr A RAMAZZOTTI

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Detailed information

Clinical genetics review
  • EN (2009)
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